KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy

Tawfeeq Shekh-Ahmad, Ramona Eckel, Sharadha Dayalan Naidu, Maureen Higgins, Masayuki Yamamoto, Albena Dinkova-Kostova, Stjepana Kovac, Andrey Y. Abramov (Lead / Corresponding author), Matthew C. Walker (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    92 Citations (Scopus)
    277 Downloads (Pure)


    Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.

    Original languageEnglish
    Pages (from-to)1390-1403
    Number of pages14
    Issue number5
    Early online date12 Mar 2018
    Publication statusPublished - May 2018


    • epilepsy
    • epileptogenesis
    • mitochondrial dysfunction
    • Nrf2-KEAP1 pathway
    • oxidative stress

    ASJC Scopus subject areas

    • Clinical Neurology


    Dive into the research topics of 'KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy'. Together they form a unique fingerprint.

    Cite this